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Nat Med. 2020 Jan;26(1):98-109. doi: 10.1038/s41591-019-0705-y. Epub 2020 Jan 13.

Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.

Author information

1
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
2
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
4
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
5
Clare Hall, University of Cambridge, Cambridge, UK.
6
Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
7
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
8
Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
9
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
10
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. ela.knapik@vumc.org.
11
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. ela.knapik@vumc.org.
12
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. ela.knapik@vumc.org.

Abstract

Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.

PMID:
31932796
DOI:
10.1038/s41591-019-0705-y

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